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Multiscale simulations reveal TDP-43 molecular-level interactions driving condensation
Helgi I Ingólfsson1, Azamat Rizuan2, Xikun Liu3
1Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California.
Biophysical Journal
|October 19, 2023
Summary
Molecular dynamics simulations reveal that the protein TDP-43, implicated in neurodegenerative diseases like ALS, dynamically associates with itself and other molecules, driving the formation of cellular condensates.
Area of Science:
- Neuroscience
- Biochemistry
- Computational Biology
Background:
- TDP-43 protein is crucial for mRNA processing and transport.
- Cytoplasmic aggregation of TDP-43 is a hallmark of neurodegenerative diseases, including ALS.
- The role of TDP-43 accumulation in neurodegeneration remains unclear.
Purpose of the Study:
- To investigate the self- and cross-interaction dynamics of TDP-43 using molecular dynamics simulations.
- To explore TDP-43 interaction patterns at various resolutions.
Main Methods:
- Constructed a full-length molecular model of TDP-43 (414 amino acids).
- Employed multi-resolution molecular dynamics simulations (all-atom CHARMM36m and coarse-grained Martini 3).
- Simulated single TDP-43 proteins, pairs, and large assemblies to analyze interactions.
Main Results:
- TDP-43 exhibits numerous, dynamic interaction preferences.
- The protein shows a strong, yet flexible, tendency to associate with itself and other molecules.
- These interactions drive the formation of biomolecular condensates.
Conclusions:
- Multi-resolution simulations are effective for studying TDP-43 interactions.
- TDP-43's dynamic association patterns contribute to condensate formation.
- Understanding these dynamics may offer insights into TDP-43's role in neurodegeneration.
